title: Semaphorin 4F as a critical regulator of neuroepithelial interactions and a biomarker of aggressive prostate cancer.
abstract: BACKGROUND
  Semaphorin 4F (S4F) has roles in embryologic axon guidance and is expressed in adults. S4F is involved in cancer-induced neurogenesis.
  
  
  METHODS
  Prostate cells were transfected with S4F retrovirus. Cells and controls were used for a bromodeoxyuridine (BrdUrd) incorporation assay (proliferation) and in vitro scratch and Matrigel Transwell chamber invasion assay (migration). Monoclonal antibodies were developed using baculovirus-expressed recombinant GST-S4F and used to immunostain tissue microarrays. Slides were imaged using deconvolution and analyzed using tissue segmentation. Data were correlated with clinicopathologic parameters, other biomarkers and survival analysis conducted. Heterogeneity of S4F expression was analyzed with unsupervised clustering algorithms.
  
  
  RESULTS
  Proliferation rates measured by BrdUrd incorporation were higher in all S4F-transfected cells. S4F overexpression was associated with increased motility of the cancer cells. S4F expression was overexpressed in high-grade prostatic intraepithelial neoplasia/prostate cancer than normal epithelium. S4F expression correlated with seminal vesicle invasion. Patients with high values of S4F in prostate cancer cytoplasm are at significantly higher risk of biochemical recurrence, by univariate and multivariate analyses. S4F cytoplasmic expression in prostate cancer cells also correlates with nerve density in prostate cancer and perineural invasion diameter. Correlations were identified with NF-κB and inversely with apoptosis in perineural invasion.
  
  
  CONCLUSIONS
  These data show that S4F is significantly involved in human prostate cancer progression. S4F is a key regulator of the interactions between nerves in the tumor microenvironment and cancer cells. Because of the importance of cancer nerve interaction in the biology of cancer and its clinical implication, S4F can be considered a major therapeutic target. Clin Cancer Res; 19(22); 6101-11. ©2013 AACR.
authors.affiliation: Authors' Affiliations: Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center Medical School; Departments of Pathology & Immunology and Molecular & Cell Biology, Dan L. Duncan Cancer Center, Scott Department of Urology, Baylor College of Medicine; Department of Urology, The Methodist Hospital, Houston, Texas; and Department of Internal Medicine, Detroit Medical Center, Sinai-Grace Hospital, Wayne State University, Detroit, Michigan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Dandan
authors.initials: D
authors.lastname: He
authors.forename: Diego
authors.initials: D
authors.lastname: Florentin
authors.forename: Anna
authors.initials: A
authors.lastname: Frolov
authors.forename: Sue
authors.initials: S
authors.lastname: Hilsenbeck
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
authors.forename: Dov
authors.initials: D
authors.lastname: Kadmon
authors.forename: Brian
authors.initials: B
authors.lastname: Miles
authors.forename: David
authors.initials: D
authors.lastname: Rowley
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ayala
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D046569:Neuroepithelial Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D039961:Semaphorins / Q000378:metabolism*; D012669:Seminal Vesicles / Q000166:cytology / Q000473:pathology; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C118124:SEMA4F protein, human; D039961:Semaphorins